EP3194374B1 - Triazole compounds as t-type calcium channel blockers - Google Patents

Triazole compounds as t-type calcium channel blockers Download PDF

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EP3194374B1
EP3194374B1 EP15763321.5A EP15763321A EP3194374B1 EP 3194374 B1 EP3194374 B1 EP 3194374B1 EP 15763321 A EP15763321 A EP 15763321A EP 3194374 B1 EP3194374 B1 EP 3194374B1
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acetamide
benzyl
triazol
phenyl
fluoro
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EP3194374A1 (en
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Olivier Bezencon
John Gatfield
Bibia HEIDMANN
Romain Siegrist
Simon STAMM
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Idorsia Pharmaceuticals Ltd
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel triazole compounds and their use as T-type calcium channel blockers in the treatment or prevention of various diseases or disorders where calcium T channels are involved, to pharmaceutical compositions containing these derivatives, and to processes for their preparation.
  • VOCs voltage-gated calcium channels
  • the L, N, P and Q-type channels activate at more positive potentials (high voltage activated) and display diverse kinetics and voltage-dependent properties.
  • the T-type class (or "low voltage-activated") is characterized by fast inactivation (transient) and small conductance (tiny) and is composed of three members due to the different main pore-forming ⁇ 1 subunits: Cav3.1 ( ⁇ 1 G), Cav3.2 ( ⁇ 1 H) and Cav3.3 ( ⁇ 1 I).
  • Electrodegenerative disorders such as especially epilepsy, pain, neuropathic pain, sleep disorders, sleep disturbances, schizophrenia, essential tremors, Parkinson's disease, neurodegenerative disorders, depression, anxiety, psychosis, autism, drug addiction, hypertension, cardiac arrhythmias, heart block, cancer, diabetes, infertility and sexual dysfunction ( Bourinet, E.; Alloui, A.; Monteil, A.; Barrere, C.; Couette, B.; Poirot, O.; Pages, A.; McRory, J.; Snutch, T.
  • T-type calcium channels are essential for regulating neuronal excitability and burst firing, both in the central and peripheral nervous system ( Lambert, R. C.; Bexcellenth, T.; Crunelli, V.; Leresche, N., Pflugers Arch 2014, 466 (3), 415-23 .). They are linked to diseases or disorders where abnormal oscillatory activity occurs in the brain, as well as diseases or disorders where there is abnormal coupling of activity, particular through the thalamus. They are particularly linked to an increasing number of neurological disorders such as the epilepsy disorders and neuropathic pain.
  • T-type calcium channels play a role in regulating neuronal firing patterns under normal physiological conditions, such as during sleep rhythms ( Anderson, M. P.; Mochizuki, T.; Xie, J.; Fischler, W.; Manger, J. P.; Talley, E. M.; Scammell, T. E.; Tonegawa, S., Proc Natl Acad Sci U S A 2005, 102 (5), 1743-8 ; Destexhe, A.; Contreras, D.; Sejnowski, T. J.; Steriade, M., J Neurophysiol 1994, 72 (2), 803-18 ; Lee, J.; Kim, D.; Shin, H.
  • T-type calcium channels are also involved in pathophysiological conditions such as epilepsy, autism, hypertension, atrial fibrillation, congenital heart failure, pain, psychoses and cancer (for review, see Iftinca, M. C., J Med Life 2011, 4 (2), 126-38 ).
  • T-type calcium channels are critical players in the development of idiopathic generalized seizures in humans and animals ( Cheong, E.; Shin, H. S., Pflugers Arch 2014, 466 (4), 719-34 ; Khosravani, H.; Zamponi, G. W., Physiol Rev 2006, 86 (3), 941-66 ; Zamponi, G. W.; Lory, P.; Perez-Reyes, E., Pflugers Arch 2010, 460 (2), 395-403 ).
  • knockout of Cav3.1 calcium channels protects mice from absence seizures ( Kim, D.; Song, I.; Keum, S.; Lee, T.; Jeong, M. J.; Kim, S. S.; McEnery, M.
  • T-type calcium currents were uppregulated after status epilepticus and suggest a role of this channel in long-lasting modification of neuronal firing mode (regular to burst firing) and potential contribution to the development and expression of an epileptic condition after SE ( Yaari, Y.; Yue, C.; Su, H., J Physiol 2007, 580 (2), 435-50 ; Becker, A. J.; Pitsch, J.; Sochivko, D.; Opitz, T.; Staniek, M.; Chen, C. C.; Campbell, K.
  • T-type calcium channel has been associated to neuropathic and inflammatory pain states (for review, see Todorovic, S. M.; Jevtovic-Todorovic, V., Br J Pharmacol 2011, 163 (3), 484-95 ).
  • nociceptors When nociceptors are in an increased state of responsiveness, they often respond to normal sensory stimuli as if painful (allodynia) and to mildly painful stimuli as though they were acutely painful (hyperalgesia).
  • the electrophysiological answer of these altered pain responses include lower thresholds of activation, increased frequency of firing in response to suprathreshold stimuli and spontaneous firing ( Coderre, T. J.; Katz, J.; Vaccarino, A.
  • T-type calcium channel are abundantly expressed in nociceptors, spinal dorsal horn and thalamic neurons ( Talley, E. M.; Cribbs, L. L.; Lee, J. H.; Daud, A.; Perez-Reyes, E.; Bayliss, D. A., J Neurosci 1999, 19 (6), 1895-911 ) and increased T-type channel activity has been linked to neuropathic and inflammatory pain states in animals and humans ( Jagodic, M.
  • T-channels may play a role in the decrease of the threshold for action potential firing in dorsal root ganglia (DRG) cells that express T-channels ( Nelson, M. T.; Todorovic, S. M.; Perez-Reyes, E., Curr Pharm Des 2006, 12 (18), 2189-97 ; Jagodic, M. M.; Pathirathna, S.; Nelson, M. T.; Mancuso, S.; Joksovic, P. M.; Rosenberg, E. R.; Bayliss, D.
  • DDG dorsal root ganglia
  • T-type calcium channels would play a role of amplifiers of peripheral pain signals.
  • Pharmacological and molecular downregulation of the function of these channels in DRG neurons supports the notion that T-channels contribute to the chronic pain associated with peripheral axonal injury ( Bourinet, E.; Alloui, A.; Monteil, A.; Barrere, C.; Couette, B.; Poirot, O.; Pages, A.; McRory, J.; Snutch, T.
  • T-type calcium channel activity is upregulated during diabetic neuropathy ( Hall, K. E.; Sima, A. A.; Wiley, J. W., J Physiol 1995, 486 (2), 313-22 ; Jagodic, M. M.; Pathirathna, S.; Nelson, M. T.; Mancuso, S.; Joksovic, P. M.; Rosenberg, E. R.; Bayliss, D. A.; Jevtovic-Todorovic, V.; Todorovic, S. M., J Neurosci 2007, 27 (12), 3305-16 ).
  • T-type calcium (Ca) channels in the CNS are closely associated with repetitive burst discharges or neuronal oscillations ( Llinas, R.; Yarom, Y., J Physiol 1986, 376, 163-82 ; Gutnick, M. J.; Yarom, Y., J Neurosci Methods 1989, 28 (1-2), 93-9 ; Iftinca, M. C.; Zamponi, G. W., Trends Pharmacol Sci 2009, 30 (1), 32-40 ).
  • Tremor is a common encountered involuntary movements, and it is associated with various neurological diseases or pathological conditions such as essential tremor (ET) and Parkinson's disease (PD) and its related disorders.
  • T-type Ca channels As tremor-related neuronal activities may be closely related to repetitive or oscillatory activities in the CNS, controlling T-type Ca channels may have therapeutic effects. This hypothesis is supported by neuro-anotomical and functional expression of expression of T-type calcium channels in area involved pathophysiological mechanisms underlying harmaline-induced tremor, a pharmacological model of ET in rodents ( Llinas, R.; Yarom, Y., J Physiol 1986, 376, 163-82 ; Cavelier, P.; Lohof, A. M.; Lonchamp, E.; Beekenkamp, H.; Mariani, J.; Bossu, J. L., Neuroreport 2008, 19 (3), 299-303 ).
  • Parkinson's disease (PD) patients deep brain stimulation of the subthalamic nucleus has been shown to be an effective treatment for parkinsonian symptoms indicating a pivotal role of this area in the pathogenesis of PD: In patients, as well as in animal models of PD, this area seems to have an abnormal pattern of firing with an increase of the burst firing mode. And this burst firig mode has been shown to involve the T-type Ca 2+ channels (for review, see Yang, Y. C.; Tai, C. H.; Pan, M. K.; Kuo, C. C., Pflugers Arch 2014, 466 (4), 747-55 ).
  • WO 2010/122088 discloses certain 2-benzyl-triazole derivatives as CRAC channel inhibitors.
  • the compounds of the present invention are potent calcium T channel blockers and therefore useful for the prevention or treatment of diseases or disorders where calcium T channels are involved.
  • the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • the compounds of the present invention may be present in tautomeric forms. Any such tautomeric form is encompassed.
  • a benzimidazole moiety is unsubstituted on the ring nitrogen having a free valency such benzimidazole moiety represents tautomeric forms.
  • further substituents of the benzimidazole moiety may be attached in the position(s) ortho to the bridgehead atoms (i.e. attached in position(s) 4 and/or 7), and/or in the position(s) meta to the bridgehead atoms, (i.e. attached in position(s) 5 and/or 6).
  • the two ortho , and, respectively, the two meta positions are considered equivalent.
  • the group 4-methyl-1H-benzoimidazol-2-yl is understood to signify the same group as 7-methyl-1H-benzoimidazol-2-yl and 4-methyl-3H-benzoimidazol-2-yl and 7-methyl-3H-benzoimidazol-2-yl.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) according to embodiments 1) to 18), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g.
  • the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • variably attached bonds may be used for substituents or groups (e.g. (R 4 ) n and (R 5 ) m ) .
  • substituents or groups e.g. (R 4 ) n and (R 5 ) m
  • any such substituent or group may be attached to any carbon atom of the ring system to which the variable attached bond is drawn into, provided that said carbon atom is not already substituted.
  • a bond drawn as a dotted line shows the point of attachment of the radical drawn.
  • the radical drawn below is a 2 H -triazol-2,4-diyl group.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects.
  • Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • Handbook of Pharmaceutical Salts. Properties, Selection and Use P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 ; and " Pharmaceutical Salts and Co-crystals", Johan Wouters and Luc Qucha (Eds.), RSC Publishing, 2012 .
  • halogen means fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine, especially fluorine.
  • cyano refers to a group -CN.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing one to six (especially one to four) carbon atoms.
  • (C x-y )alkyl refers to an alkyl group as defined before, containing x to y carbon atoms.
  • a (C 1-y )alkyl group or, in general, a (C x-y )alkyl group
  • the term means that said substituent is linked through a (C 1-y )alkyl group (or a (C x-y )alkyl group, respectively) to the rest of the molecule.
  • such group is also referred to as (C 1-y )alkylene.
  • a (C 1-6 )alkyl group contains from one to six carbon atoms.
  • Examples of (C 1-6 )alkyl groups are the (C 1-4 )alkyl groups methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, and isobutyl, as well as n-pentyl, and isopentyl.
  • Preferred are methyl, ethyl, n-propyl, and isopropyl. Most preferred is methyl.
  • For the substituent R 1 preferred examples of (C 2-6 )alkyl are isopropyl, tert .-butyl, and isobutyl; especially tert .-butyl.
  • Examples of (C 2-4 )alkyl groups which are mono-substituted with cyano, or (C 1-3 )alkoxy as used for R 1 are 1-methoxy-ethyl, and 1-cyano-1-methyl-ethyl.
  • alkoxy means a group of the formula alkyl-O- in which the term alkyl has the previously given significance.
  • (C x-y )alkoxy (x and y being an integer) refers to a straight or branched chain alkoxy group containing x to y carbon atoms. Examples of alkoxy groups are the (C 1-4 )alkoxy groups methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. Preferred is methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (C 1-3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • a preferred example is trifluoromethyl.
  • Examples of (C 2-3 )fluoroalkyl groups include 2-fluoroethyl and 2,2,2-trifluoroethyl.
  • the fluoroalkyl group contains from one to four carbon atoms in which one to nine hydrogen atoms have been replaced with fluorine.
  • Examples of (C 1-4 )fluoroalkyl groups as used for R 1 include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro-1,1 -dimethyl-ethyl; especially trifluoromethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (C 1-3 )fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • Preferred examples are trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy.
  • fluoroalkoxy groups as used for R 1 include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy; especially 2,2,2-trifluoroethoxy.
  • cycloalkyl refers to a saturated mono- or bicyclic carbocyclic ring containing three to eight carbon atoms.
  • (C x-y )cycloalkyl (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms.
  • a (C 3-6 )cycloalkyl group refers to a saturated monocyclic carbocyclic ring containing three to six carbon atoms.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred is cyclopropyl.
  • (C 3-6 )cycloalkyl wherein the cycloalkyl may optionally contain a ring oxygen atom
  • one ring carbon atom of said cycloalkyl may be replaced by an oxygen atom.
  • substituent R 1 examples of such groups are especially cyclopropyl, cyclobutyl, and, in addition, oxetan-3-yl. Said groups are unsubstituted or substituted as explicitly defined.
  • (C 3-6 )cycloalkyl-(C 1-3 )alkyl refers to a (C 3-6 )cycloalkyl group as explicitly defined which group is linked to the rest of the molecule through a (C 1-3 )alkylene group as defined before.
  • the (C 1-2 )alkylene group part of (C 3-6 )cycloalkyl-(C 1-2 )alkyl is in particular a methylene group.
  • (C 3-6 )cycloalkyl-oxy refers to a (C 3-6 )cycloalkyl group as explicitly defined which is linked to the rest of the molecule through an oxygen atom.
  • (C 3-6 )cycloalkyl-(C 1-2 )alkylene-oxy refers to a (C 3-6 )cycloalkyl group as explicitly defined which is linked to the rest of the molecule through a -(CH 2 ) 1-2 -O- group.
  • the -(C 1-2 )alkylene-oxy group part of (C 3-6 )cycloalkyl-(C 1-2 )alkylene-oxy is in particular a -CH 2 -O- group.
  • (C 1-3 )alkoxy-(C 2-3 )alkoxy refers to a (C 1-3 )alkoxy-group as defined before which is attached to the rest of the molecule through a (C 2-3 )alkoxy group as defined before.
  • An example is 2-methoxy-ethoxy.
  • (C 1-3 )alkoxy-(C 2-3 )alkyl means a (C 1-3 )alkoxy-group as defined before which is attached to the rest of the molecule through a (C 2-3 )alkylene group as defined before.
  • An example is 2-methoxy-ethyl.
  • aryl used alone or in combination, means phenyl or naphthyl, preferably phenyl.
  • an arylene group is an aryl group as defined before having two points of attachment to the respective rests of the molecule.
  • the above-mentioned aryl / arylene groups are unsubstituted or substituted as explicitly defined.
  • heteroaryl used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are 5-membered heteroaryl such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl; 6-membered heteroaryl such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and bicyclic heteroaryl such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl,
  • bicyclic heteroaryl rings are pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, indolyl, indazolyl, quinoxalinyl, benzoimidazolyl, and quinolinyl; especially pyrazolo[3,4-b]pyridinyl, indolyl, and indazolyl.
  • the above-mentioned groups do not carry further substituents on the phenyl / pyridine part of the ring, whereas said aromatic 5- or 6-membered ring may be unsubstituted or substituted as explicitly defined.
  • examples of such thus formed bicyclic partially aromatic rings are 2,3-dihydro-benzooxazolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydro-1H-indolyl, and 2,3-dihydro-benzofuranyl; especially 2,3-dihydro-1H-indolyl.
  • the above-mentioned groups do not carry further substituents on the phenyl / pyridine part of the ring, whereas said non-aromatic 5- or 6-membered ring may be unsubstituted or substituted as explicitly defined.
  • Examples of -NR 11 R 12 groups as used for R 1 are especially disubstituted amino groups wherein one substituent is methyl or ethyl, and the other is (C 1-3 )alkyl, (C 2-3 )fluoroalkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl mono- or di-substituted with fluoro, (C 3-6 )cycloalkyl-(C 1-3 )alkyl, (C 1-3 )alkoxy-(C 2-3 )alkyl.
  • Examples are dimethylamino, ethyl-methyl-amino, diethylamino, cyclopropyl-methyl-amino, (2-methoxyethyl)-methyl-amino, (cyclopropylmethyl)-methyl-amino, and (2,2-difluoro-ethyl)-methyl-amino; preferred examples are dimethylamino, diethylamino, cyclopropyl-methyl-amino, and (cyclopropylmethyl)-methyl-amino.
  • Examples of -NR 11 R 12 groups wherein R 11 and R 12 together with the nitrogen atom to which they are attached to form a 4-to- 6 membered ring as used for R 1 are especially the four and five-membered rings azetidinyl, 3-fluoro-azetidinyl, 3,3-difluoro-azetidinyl, pyrrolidinyl (preferred), 3-fluoro-pyrrolidinyl, 3,3-difluoro-pyrrolidinyl (preferred).
  • the compounds of formula (I) according to embodiments 1) to 19) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins ]) by bringing the described compounds of formula (I), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any one of embodiments 1) to 19).
  • the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
  • the term “about” (or alternatively the term “around”) placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
  • the compounds of formula (I) as defined in any one of embodiments 1) to 19) are useful for the prevention or treatment of diseases or disorders where calcium T channels are involved.
  • Such diseases or disorders where calcium T channels are involved may be defined as including especially:
  • diseases or disorders where calcium T channels are involved refer to epilepsy, neurological disorders, and pain.
  • diseases or disorders refer to epilepsy and pain.
  • epilepsy describes recurrent unprovoked seizures wherein the term “seizure” refers to an excessive and/or hypersynchronous electrical neuronal activity.
  • Different types of “epilepsy” are disclosed for example in [ Berg et al., Epilepsia. 2010; 51(4): 676-685 ], which reference is herewith incorporated by reference.
  • the term “epilepsy” as used herein preferably refers to absence epilepsy, childhood absence and other forms of idiopathic generalized epilepsies, temporal lobe epilepsy.
  • pain preferably refers to inflammatory pain, neuropathic pain, peripheral pain, and chronic pain associated with peripheral axonal injury.
  • neurodegenerative disorders preferably refers to essential tremors, Parkinson's disease, schizophrenia, depression, anxiety, psychosis, neurodegenerative disorders,autism, drug addiction.
  • cardiac diseases and disorders preferably refers to hypertension, cardiac arrhythmias, atrial fibrillation, congenital heart failure, heart block.
  • the compounds of formula (I) as defined in embodiments 1) to 19) are also useful in a method of reducing the concentration of calcium in a neuronal cell, and wherein said reduction in calcium is achieved by blocking the calcium T-channel present in such neuronal cell; said method comprising the administration of a compound of formula (I) as defined in embodiments 1) to 19).
  • the compounds of formula (I) as defined in embodiments 1) to 19) are also useful in a method of decreasing burst firing discharges in a neuronal cell and wherein said decrease of burst firing is achieved by blocking the calcium T-channel; said method comprising the administration of a compound of formula (I) as defined in embodiments 1) to 19).
  • the compounds of formula (I) can be prepared by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
  • the generic groups X, Y, R 1 , R 2 , (R 4 ) n , and (R 5 ) m are as defined for the compounds of formula (I).
  • the generic groups R 1 , R 2 , (R 4 ) n , and (R 5 ) m may be incompatible with the assembly illustrated in the schemes and so will require the use of protecting groups (PG).
  • protecting groups are well known in the art (see for example " Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999 ). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place.
  • the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts in a manner known per se.
  • Compounds of formula (I) can be prepared via an amide coupling as final step (Scheme 1).
  • the corresponding carboxylic acid (IV) can be activated to the corresponding acid chloride, typically with oxalyl chloride.
  • the carboxylic acid (IV) can be directly coupled to the amine (III) using a coupling reagent, typically HATU or HBTU. In certain instances two coupling products can be formed and are separated by preparative HPLC.
  • the desired primary aminotriazole (III) can be prepared from the corresponding nitrotriazole (V) through an alkylation (compound of type (VI)) and a reduction step.
  • an alkylation compound of type (VI)
  • zinc or iron are preferentially used.
  • Aminotriazoles of type (III) can be prepared via a Curtius rearrangement as well (Scheme 3).
  • a suitable ester from the triazole-3-carboxylic acid (VIII) can be alkylated to compound (IX). Saponification leads to carboxylic acid (X), and subsequent Curtius rearrangement leads to the aminopyrazole (III).
  • a third possibility to prepare a compound of type III starts from 4,5-dibromo-2H-1,2,3-triazole (Scheme 4).
  • An N-alkylation leads to a compound of type (XI).
  • the selective reduction of a bromide with, for instance, i PrMgCl P. Wipf et al., Org. Lett. 2010, 12(20), 4632-4635 ) leads to a compound of type (XII), and an Ullman amination leads to a compound of type (III)
  • the carboxylic acids of type (IV) can be prepared according to known procedures.
  • a Negishi coupling (Scheme 5) or a similar carbon-carbon coupling between an (hetero)aryl bromide of type (XIII) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide leads to the ester of type (XIV):
  • Hydrolysis generally under acidic conditions, leads to the acid of type (IV).
  • Bromide of type (XIII) is either commercially available, or can be prepared according to known procedures (see experimental part).
  • a benzoic acid of type (XV) can be transformed into an acid of type (IV) via a Wolff rearrangement (Scheme 6).
  • the acid of type (XV) can be reduced to an alcohol of type (XVI).
  • This alcohol can then be activated to a compound of type (XVII), wherein LG represents a leaving group such as chloride, bromide, mesylate of tosylate, and homologated to nitrile of type (XVIII): Hydrolysis would then lead to the acid of type (IV).
  • substituents R 1 , R 2 , R 4 and / or R 5 can be present as precursors in the starting material, and can be transformed by additional routine transformations during the synthetic pathways presented herein.
  • the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m), IC (5 ⁇ m) or AD-H (5 ⁇ m) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m), IC (5 ⁇ m) or AD-H (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane), at a flow rate of 0.8 to 150 mL/min.
  • eluent A EtOH, in presence or absence of an amine such as triethylamine or diethylamine
  • eluent B heptane
  • Reaction mixture can often be separated by preparative HPLC. A person skilled in the art will find suitable conditions for each separation.
  • the mixture is stirred at 0 °C for 1 h then at rt for 3 h.
  • the mixture is heated up to 40 °C, and stirred at that temperature overnight.
  • the mixture is quenched by the addition of sat. aq. NaHCO 3 sol., and is extracted with CH 2 Cl 2 (3x).
  • the comb. org. layers are washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo to give the crude title product.
  • the mixture can be heated up to 60 °C.
  • the mixture is partitioned between aq. sat. NaHCO 3 and EtOAc.
  • the aq. layer is extracted with EtOAc (3x).
  • the combined org. layers are washed with brine (1x), dried over MgSO 4 , filtered, and the solvents are removed under reduced pressure.
  • Purification of the residue by automated FC (silicagel, EtOAc / heptane) or reversed phase HPLC (CH 3 CN / water) yields the desired methyl or ethyl 2-benzyl-2H-1,2,3-triazole-4-carboxylate derivative.
  • Aq. 1M LiOH (4 - 5 eq.) is added to a sol. of the desired methyl or ethyl 2-benzyl-2H-1,2,3-triazole-4-carboxylate derivative (1 eq.) in a 5:1-mixture of THF and MeOH (0.05 M). The mixture is stirred at rt after consumtion of the starting material (1 h - overnight). The solvents are partially removed under reduced pressure, and the residue is acidified to pH 4 with aq. 2M HCl. Continuous extraction with CH 2 Cl 2 leads to an org. layer that is dried over MgSO 4 , and filtered.
  • TEA (2 eq.) and (PhO) 2 P(O)N 3 (1.2 eq.) are added to a sol. of the desired 2-benzyl-2H-1,2,3-triazole-4-carboxylic acid derivative (1 eq.) in toluene (0.05 - 0.1 M) at rt.
  • the mixture is heated to 80 °C under stirring, and Me 3 Si(CH 2 ) 2 OH (1.5 eq.) is added.
  • the mixture is stirred at 90 - 100 °C until consumption of the starting materials (2 - 4 h).
  • the mixture is allowed to cool to rt, and the solvents are removed under reduced pressure.
  • TBAF (1.5 eq.) is added slowly to a sol. of the desired 2-(trimethylsilyl)ethyl (2-benzyl-2H-1,2,3-triazol-4-yl)carbamate derivative (1 eq.) in THF (0.25 - 0.5 M) at 0 °C.
  • the mixture is stirred until consumption of the starting material (1 h - 24 h) while warming up to rt.
  • the mixture was partitioned between EtOAc and aq. 10% Na 2 CO 3 .
  • the org. layer is washed with aq. 10% Na 2 CO 3 (4x), dired over MgSO 4 , filtered, and the solvents are removed under reduced pressure to yield the desired 2-benzyl-2H-1,2,3-triazol-4-amine.
  • Methyl 2-(4-(vinyloxy)phenyl)acetate A mixture of methyl-4-hydroxyphenylacetate (1.66 g, 10 mmol), vinyl acetate (1.84 mL, 20.0 mmol), chloro(1,5-cyclooctadiene)iridium(I) dimer (133 mg, 0.20 mmol), and Na 2 CO 3 (636 mg, 6.00 mmol) in toluene (10 mL) is stirred at 100 °C for 2.5 h. Subsequently, water is added, and the mixture is extracted with EtOAc. The combined org. layers are washed with brine, dried over MgSO 4 , and concentrated under reduced pressure.
  • 3-(4-Bromophenyl)-3-methoxyoxetane 3-(4-Bromophenyl)oxetan-3-ol ( WO2008156726 , 150 mg, 0.65 mmol) is dissolved in DMF (2.00 mL). The mixture is cooled to 0 °C, and NaH (29 mg, 0.72 mmol) is added. The mixture is stirred for 1 h at 0 °C, and Mel (0.05 ml, 0.79 mmol) is added. The mixture is stirred at rt over 3 days. Water is added. The mixture is extracted with ether. The combined org. extracts are dried over MgSO 4 , filtered, and the solvents are removed under reduced pressure under reduced pressure.
  • Oxetan-3-ylmethyl 4-methylbenzenesulfonate p-Toluenesulfonyl chloride (370 mg, 1.94 mmol) is dissolved in pyridine (1.62 mL, 20 mmol). 3-Oxetanemethanol (150 mg, 1.62 mmol) is added. The sol. is stirred at rt for 3 h. The sol. is diluted with EtOAc, and washed with aq. 0.1 M HCl and with aq. sat. NaHCO 3 . The org. layer is dried over Na 2 SO 4 , filtered, and the solvents are removed under reduced pressure.
  • 5-Bromo-3-fluoro-2-(pyrrolidin-1-yl)pyridine To a sol. of 5-bromo-2,3-difluoropyridine (680 mg, 3.51 mmol) in DMSO (20 mL), are added pyrrolidine (0.307 mL, 3.68 mmol) and then DBU (1.10 mL, 7.36 mmol). The mixture is heated to 80 °C and stirred at this temperature for one day. The mixture is allowed to cool down to rt. The mixture is diluted with aq. sat. NaHCO 3 (200 mL) and EtOAc (200 mL). The layers are separated, and the aq. layer is extracted with EtOAc (1x 100 mL).
  • Methyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)acetate To an ice-cooled sol. of methyl 4-hydroxy-3-methylphenylacetate (0.33 mL, 2 mmol) and CS 2 CO 3 (1.30 g, 4.00 mmol) in DMF (5.3 mL), is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.46 mL, 3.0 mmol). The mixture is stirred at rt over 3 days while warming up to rt. The mixture is partitioned between water (10 mL) and EtOAc (10 mL). The layers are separated. The aq.
  • a sol. of the tert-butyl arylacetate in an acid (HCl/dioxane, or HCOOH) with optionally CH 2 Cl 2 is prepared at 0 °C. This mixture is stirred at 0 °C, optionally warming up to rt, until consumption of the starting material. The solvents are removed under reduced pressure to yield the crude desired arylacetic acid derivative.
  • Example number Product name LC-MS t R (min.), MH + , conditions 1 N-[2-(4-Fluoro-benzyl)-2H-[1,2,3]triazol-4-yl]-2-(4-isopropyl-phenyl)-acetamide 0.95, 353.26, cond. 3 2 2-(4-Dimethylamino-phenyl)-N-[2-(4-fluoro-benzyl)-2H-[1,2,3]triazol-4-yl]-acetamide 0.57, 354.23, cond.
  • 3 160 N-[2-(4-Cyano-3-fluoro-benzyl)-2H-[1,2,3]triazol-4-yl]-2-[6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-acetamide 0.62, 422.15, cond.
  • 3 161 N-[2-(4-Cyano-3-fluoro-benzyl)-2H-[1,2,3]triazol-4-yl]-2-(5-fluoro-6-pyrrolidin-1-yl-pyridin-3-yl)-acetamide 0.68, 424.18, cond.
  • 5 206 N-[2-(3-Cyano-4-methyl-benzyl)-2H-[1,2,3]triazol-4-yl]-2-[4-(3-methoxy-oxetan-3-yl)-phenyl]-acetamide 0.98, 418.3, cond. 5 207 N-[2-(3-Cyano-4-methoxy-benzyl)-2H-[1,2,3]triazol-4-yl]-2-[6-(3,3-difluoro-pyrrolidin-1-yl)-pyridin-3-yl]-acetamide 0.71, 454.3, cond.
  • 5 214 N-[2-(3-Cyano-4-methoxy-benzyl)-2H-[1,2,3]triazol-4-yl]-2-[4-(3-fluoro-oxetan-3-yl)-phenyl]-acetamide 0.98, 422.3, cond.
  • 5 215 N-[2-(3-Cyano-4-methyl-benzyl)-2H-[1,2,3]triazol-4-yl]-2-(1-methyl-1H-indazol-6-yl)-acetamide 0.97, 386.3, cond.
  • 5 236 N-[2-(3-Cyano-4-methoxy-benzyl)-2H-[1,2,3]triazol-4-yl]-2-(6-pyrrolidin-1-yl-pyridin-3-yl)-acetamide 0.58, 418.3, cond.
  • 5 237 N-[2-(4-Cyano-benzyl)-2H-[1,2,3]triazol-4-yl]-2-[4-(3-methoxy-oxetan-3-yl)-phenyl]-acetamide 1.07, 404.0, cond.
  • 5 240 N-[2-(3,4-Difluoro-5-methoxy-benzyl)-2H-[1,2,3]triazol-4-yl]-2-(1,3-dimethyl-1H-indol-5-yl)-acetamide 1.20, 426.3, cond. 5 241 N-[2-(4-Cyano-3-methyl-benzyl)-2H-[1,2,3]triazol-4-yl]-2-[4-(1-trifluoromethyl-cyclopropyl)-phenyl]-acetamide 1.55, 457.2 (2) , cond.
  • HEK293 cells recombinantly expressing either voltage-dependent T-type calcium channel subunit alpha-1G (Cav3.2) or voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2) are assayed for calcium flux using the calcium indicator dye Fluo-4-AM (Molecular Devices) and FLIPR technology (Fluorometric Imaging Plate Reader, Molecular Devices) ( Xie X, Van Deusen AL, Vitko I, Babu DA, Davies LA, Huynh N, Cheng H, Yang N, Barrett PQ, Perez-Reyes E. Validation of high throughput screening assays against three subtypes of Ca(v)3 T-type channels using molecular and pharmacologic approaches.
  • the HEK293 cells recombinantly expressing Cav3.2 are maintained in DMEM growth medium (Life Technologies) supplemented with 10 % Fetal Bovine Serum (FBS), 100 U/ml penicilin (Life Technologies), 100 ⁇ g/ml streptomycin (Life Technologies) and 1 mg/ml G418 (Life Technologies).
  • HEK293 cells recombinantly expressing Cav1.2 are maintained in DMEM growth medium (Life technologies) supplemented with 10 % FBS, 0.1 mg/ml G418 (Life Technologies), 0.1 mg/ml hygromycin (Life Technologies) and 40 ug/ml zeocin (Life Technologies).
  • Cells are washed once with PBS, then dissociated in 0.25 % trypsin/EDTA (Life Technologies) and seeded into poly-D-lysine coated 384-well black, clear bottom plates (BD Biosciences) at a density of 30,000 cells/well. The seeded plates are incubated overnight at 37°C.
  • HBSS 1X 137 mM NaCl; 5.4 mM KCI; 0.25 mM Na2HPO4; 1.3 mM CaCl2; 0.4 mM MgSO4; 0.5 mM MgCl2; 0.4 mM KH2PO4, pH 7.4
  • 0.375 g/L NaHCO3, 20 mM Hepes supplemented with 3 ⁇ M Fluo-4-AM and 0.15 % Pluronic (Life Technologies).
  • the cells are then washed three times with assay buffer (HBSS 1X; 0.375 g/L NaHCO3; 20 mM Hepes; 1 % FBS; pH 7.4) and allowed to rest in 50 ⁇ l of wash buffer for 30 minutes.
  • test compounds are prepared to a concentration of 10 mM in DMSO.
  • TEAC buffer 100 mM tetraethylammonium chloride; 20 mM Hepes; 2.5 mM CaCl2; 5 mM KCI; 1 mM MgCl2; 1 % FBS; pH 7.2
  • Test compounds are added to the cells to give a 3-fold dilution range from 10 ⁇ M to 0.05 nM.
  • the compounds are incubated with the cells for 3 minutes and Ca2+ entry is stimulated by adding either CaCl2 to a final concentration of 10 mM (Cav3.2 assay) or by adding KCI to a final concentration of 20 mM (Cav1.2 assay).
  • the kinetics of fluorescence increase are recorded for every well and the area under the fluorescence trace for every compound concentration is used to generate inhibition curves using non-linear regression sigmoidal concentration-response curve analysis with in-house software.
  • IC 50 values are calculated and represent the compound concentration required to inhibit 50% of the signal that is obtained in the presence of vehicle instead of test compound.
  • Antagonistic activities (IC 50 values) of all exemplified compounds have been measured for the for the Cav3.1- and the Cav3.3-channel.
  • Antagonistic activities (IC 50 values) of all exemplified compounds are in the range of 1.7 to 970 nM with respect to Cav3.1; and in the range of 1.1 to 620 nM with respect to Cav3.3.
  • Example IC50 (nM) Example IC50 (nM)
  • Example IC50 (nM) 1 21 88 56 170 50 2 17 89 20 171 22 5 30 90 200 172 33 6 9.5 91 7.4 173 150 7 6.4 92 9.9 174 28 8 37 93 15 175 100 9 22 94 10 176 64 10 23 95 46 177 33 11 32 96 44 178 49 12 31 97 36 179 22 13 27 98 83 180 43 14 17 99 19 181 86 15 40 100 22 182 13 16 15 101 480 183 26 17 7.3 102 160 184 83 18 15 103 74 185 17 19 9.7 104 70 186 8.8 20 89 105 20 187 65 21 180 106 36 188 96 22 15 108 300 189 17 23 46 109 190 190 14 24 37 110 140 191 11 25 33 111 57 192 23 26 19 112 190 193 110 27 9.8 113 230

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